The immune system plays a central role in maintaining health and disease development. Excessive immune response leads to inflammation, which is characterized by the over-production of pro-inflammatory mediators, including lipid mediators, notably prostaglandins and leukotrienes, and cytokines like TNF-alpha, which in turn aggravate inflammation and lead to excessive damage to host tissues. During inflammation, several lipid mediators, such as prostaglandins and leukotrienes, arc synthesized from the essential fatty acid, arachidonic acid (AA), and play important roles in mediating inflammatory response. For instance, prostaglandin E2 (PGE2), which is synthesized from cyclooxygenase (COX)-catalyzed oxidation of AA, is believed to cause pain and fever as well as activate cytokine formation (44). Leukotriene B4, another oxidized product derived from AA through the 5-lipoxygenase (5-LO) catalyzed pathway in neutrophils, is a potent chemotactic agent. Important enzymes for prostaglandin formation are cyclooxygenases, which comprise a constitutive form, COX-1, and an inducible form, COX-2. COX-1 catalyzed TxA2 formation in platelets activates platelet aggregation. The protective effect of low-dose aspirin in cardiovascular disease has been attributed to its inhibition of COX-1-mediated TxA2 generation in platelets. COX-2 is normally expressed in limited tissues but is induced by endotoxin and cytokines in many immune cells including macrophages, monocytes and epithelial cells (45). Under most inflammatory conditions, COX-2 is up-regulated and is the primary enzyme responsible for the formation of pro-inflammatory PGE2. 5-LOX has also been shown to play an important role in inflammatory conditions including experimental colitis.
In addition to the lipid mediators, cytokines also play important roles in regulating inflammatory response. The major pro-inflammatory cytokines, TNF-alpha and Interleukin 1-beta (IL-1beta), are known to activate many immune cells such as monocytes and macrophages. Antibodies against TNF-alpha and IL-1beta are clinically useful in the therapy of certain inflammatory diseases (49, 50).
These pro-inflammatory mediators are also believed to be important in the development of degenerative diseases. For instance, various animal and human tumor tissues have been reported to express the enhanced COX-2 and 5-LOX, as well as their products, PGE2 and 5-HETE. PGE2 has been shown to promote proliferation of certain cancer cells, and NSAIDs can inhibit the growth of carcinoma cells and suppress angiogenesis. In addition to cancer, COX-2 and 5-LOX mediated reactions appear to play a role in cardiovascular diseases. Because of the central roles of PGE2 and LTB4 in inflammation, COXs and 5-LOX have been recognized as targets for drug therapy in inflammatory diseases.
Although drugs targeting COXs have been extensively developed and used in the treatment of inflammatory diseases, they are limited by adverse effects Inhibition of both COX-1 and COX-2 by NSAIDs and selective COX-2 inhibitors reduces the levels of prostaglandins, which leads to a reduction of pain and inflammation. However, a selective shutdown of COXs pathway can cause alternative metabolism of arachidonic acid via the 5-LOX pathway, which results in an increased production of leukotrienes, such as LTB4 and cysteinyl leukotrienes. These leukotrienes are pro-inflammatory and also known to promote gastrotoxicity. Because of the disadvantage of the selective inhibition of specific COXs pathways, a drug targeting COXs and 5-LOX, which can reduce both prostaglandins and leukotrienes, would provide a superior outcome Inhibition of these multiple pathways can not only result in a more potent anti-inflammatory effect, but also reduce potential adverse effect caused by a shunt in arachidonate metabolism to either pathway.